Borrelia miyamotoi sensu lato (Bmsl) is a newly emerging relapsing fever (RF) spirochete transmitted by the same Ixodes ticks known to transmit Lyme disease (LD) and is found in areas where LD is endemic. Bmsl has recently been demonstrated to cause human disease and manifests with symptoms ranging from a mild viral- like syndrome to chronic meningoencephalitis with cognitive and motor dysfunction. Other RF Borrelia are known to cause serious blood disorders, multiorgan system dysfunction, and fetal demise in humans, however, the full spectrum of Bmsl-associated disease is not known. A seroprevalence survey of residents in southern New England suggests that Bmsl infection rates are at least one-third those of LD. These considerations suggest that Bmsl infection may be a significant public health concern. Little is known about the epidemiology of infection and the range of clinical manifestations and complications, disease pathogenesis, or the genetic diversity of the pathogen that may impact disease expression or laboratory tests for diagnosis. Accordingly, this proposal has assembled a unique group of investigators with complementary expertise to broadly address critical gaps in our knowledge of Bmsl infection. Specifically, serosurveys and case-finding studies will be conducted in 10 study sites in the Northeast and far West regions of the United States where tick-borne diseases and Bmsl-infected ticks are prevalent. These studies will estimate seroprevalence and frequency of infection, and begin to gather additional information regarding clinical presentation and risk factors for the disease. A mouse model will be established to determine conditions of immune deficiency that may increase disease susceptibility and to evaluate whether neonatal transmission can occur and effects on maternal pregnancy and outcome. New isolates of Bmsl will be obtained from ticks in endemic foci in the Midwest, and genomic sequencing will be performed on these and other isolates from the northeast and far West to assess genetic diversity. These genetic sequences will be used to develop protein arrays to detect candidate Bmsl proteins that may be useful for diagnostic assays on serum specimens. Candidate proteins will be produced as recombinant proteins and evaluated for their utility in detecting Bmsl infection in human blood specimens. The results of these studies will provide physicians and residents living in areas endemic for tick-borne diseases important information regarding the risk for Bmsl infection. In addition, our studies will guide investigators in the field of tick-borne diseases regarding future studies on ths newly emergent human pathogen.